Preparation of 2R,3S-
View Patent ↗The present invention provides a new process for the preparation of 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride, wherein this compound is prepared directly from the chloromethylalcohol. Importantly, the process of the present invention results in higher yields of 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride without sacrificing its purity. The processes of the present invention can be used to prepare not only the 2R,3S-derivative, but also the 2S,3S-, 2S,2R- and the 2R,3R-derivatives.
1. A process for preparing a compound having the following general formula:
said process comprising:
(a) combining a halomethyl alcohol (HMA) and an amine in a halogenated solvent with aqueous bicarbonate to form a reaction mixture, and heating said reaction mixture to a temperature ranging from about 10° C. to about 50° C., wherein said HMA has the following general formula:
(b) adding to said first reaction mixture nosyl chloride while stirring said reaction mixture, and recovering the organic layer of said reaction mixture to form a solution; and
(c) reacting said solution with an acid having a pK a of less than about 4 until the reaction is complete, thereby forming the compound of Formula III;
wherein:
R 1 is an amino acid side chain or a functionalized amino acid side chain;
R 2 is a protecting group;
R 3 is a member selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and —NHP, wherein P is selected from the group consisting of H, alkyl, cycloalkyl, aryl and a protecting group;
X − is the conjugate base of said acid; and
L is a leaving group.
2. The process in accordance with claim 1 , wherein said amine is a member selected from the group consisting of primary amines, secondary amines, substituted amines, hydrazines and substituted hydrazines.
3. The process in accordance with claim 1 , wherein said amine is a member selected from the group consisting of methylamine, ethylamine, isopropylamine, n-butylamine, isobutylamine, cyclohexylamine, benzylamine, paranitrobenzylamine, dimethylamine, isobutylmethylamine, decahyroquinoline, decahydroisoquinoline, pyrimidine, isobutylhydrazine and t-Boc-hydrazine.
4. The process in accordance with claim 3 , wherein said amine is isobutylamine (IBA).
5. The process in accordance with claim 1 , wherein said halogenated solvent is a member selected from the group consisting of methylene chloride, chloroform, trifluorotoluene (oxsol), parachlorotrifluorotoluene and trichloroethylene.
6. The process in accordance with claim 1 , wherein said halogenated solvent is methylene chloride.
7. The process in accordance with claim 1 , wherein said acid is a member selected from the group consisting of HCl, HBr, CF 3 CO 2 H, CF 3 SO 3 H, CH 3 SO 3 H, H 2 SO 4 , citric acid, tartaric acid, oxalic acid and p-toluene sulfonic acid.
8. The process in accordance with claim 7 , wherein said acid is HCl.
9. The process in accordance with claim 1 , wherein said HMA is a 2S,3S-HMA.
10. The process in accordance with claim 9 , wherein said 2S,3S-HMA has the following general formula:
11. The process in accordance with claim 10 , wherein said compound of Formula III has the following general formula:
12. The process in accordance with claim 1 , wherein said reaction mixture is heated to a temperature ranging from about 30° C. to about 35° C.
13. A process for preparing a compound having the following general formula:
said process comprising:
(a) adding a compound of Formula I in a halogenated solvent with a tertiary amine and nosyl chloride to form a reaction mixture, and heating said reaction mixture at a temperature ranging from about 10° C. to about 50° C., said compound of Formula I having the following general formula:
(b) reacting said reaction mixture with an acid having a pK a of less than about 4 until the reaction is complete, thereby forming the compound of Formula III;
wherein:
R 1 is an amino acid side chain or a functionalized amino acid side chain;
R 2 is a reacting group;
R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and —NHP, wherein P is selected from the group consisting of H, alkyl, cycloalkyl, aryl and a protecting group, or R 3 and R 4 together form a cyclic structure selected from the group consisting of quinoline and isoquinoline; and
X − is the conjugate base of said acid.
14. The process in accordance with claim 13 , wherein said compound of Formula I has the following general formula:
15. The process in accordance with claim 14 , wherein said compound of Formula III has the following general formula:
16. The process in accordance with claim 13 , wherein said halogenated solvent is a member selected from the group consisting of methylene chloride, chloroform, trifluorotoluene (oxsol), parachlorotrifluorotoluene and trichloroethylene.
17. The process in accordance with claim 13 , wherein said halogenated solvent is methylene chloride.
18. The process in accordance with claim 13 , wherein said acid is a member selected from the group consisting of HCl, HBr, CF 3 CO 2 H, CF 3 SO 3 H, CH 3 SO 3 H, H 2 SO 4 , citric acid, tartaric acid, oxalic acid and p-toluene sulfonic acid.
19. The process in accordance with claim 18 , wherein said acid is HCl.
20. The process in accordance with claim 13 , further comprising washing, heating and azeotropically drying said reaction mixture prior to step (b).
21. The process in accordance with claim 13 , further comprising:
(c) recovering said compound of Formula III from said reaction mixture.
22. The process in accordance with claim 13 , wherein said reaction mixture is heated to a temperature ranging from about 30° C. to about 35° C.